Cyclization methods

ABSTRACT

The invention provides methods for cyclizing poly-yne compounds under mild conditions to provide cyclic compounds.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 61/593,127 filed on Jan. 31, 2012, which application is hereinincorporated by reference.

STATEMENT OF GOVERNMENT RIGHTS

This invention was made with government support under and R01-CA76497and R01-GM65597 awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

BACKGROUND OF THE INVENTION

Cyclic compounds, including polycyclic compounds, are useful as dyes,pesticides, pharmaceuticals, and in the electronics industry, interalia. Currently there is a need for methods that can be used to preparecyclic compounds. In particular, there is a need for methods that can becarried out under mild conditions. Such methods may be particularlyuseful for preparing complicated cyclic ring systems as well as cyclicring systems that possess sensitive functionality that may be damaged bythe conditions required by many cyclization methods. There is also aneed for methods that can lead to highly substituted cyclic ringsystems.

o-Benzyne (or 1,2-didehydrobenzene, 1, Scheme 1) is one of the oldest,most interesting, and most well studied of all reactive intermediates inchemistry. Methods for generating benzynes involve the removal of twoadjacent atoms or substituents from precursors 2. The multifaceted andoften highly efficient reactions of benzynes with suitable trappingreagents (cf. 1 to 3) have long been exploited, often in the service ofsynthetic organic chemistry. Even by 1967 myriad such reactions,recorded in a substantial monograph, were known (see Hoffmann, R. W.Organic Chemistry, A Series of Monographs—Volume 11, Academic Press, NewYork, 1967). Nonetheless, newly discovered benzyne reaction motifscontinue to emerge; this Renaissance attests to yet additionalversatility of this remarkable intermediate. Nearly all benzyne trappingreactions (regardless of whether occurring via a stepwise or anasynchronous/polarized concerted mechanistic pathway) are initiated byin-plane nucleophilic attack by electron density in the trapping agent(Nu-El) on the highly strained alkyne in 1.

The Diels-Alder [4+2] cycloaddition reaction (Scheme 2) is, arguably,the most venerable/revered reaction in all of chemistry. Theprototypical event involves addition of a 1,3-diene 4π-component (5)with an alkenyl dienophile 4 and results in a cyclohexene product 6 atthe oxidation state of a tetrahydrobenzene. If an alkyne is used as thedienophile (7), a 1,4-cyclohexadiene (or 1,4-dihydrobenzene, 8 results);this can be viewed as a didehydro-Diels-Alder reaction. Anotherwell-known variant involves engagement of a (yet more highly oxidized)1,3-enyne (9) as the 4π-component with an alkyne (7). This produces atransient cyclic allene 10 that rapidly rearranges via a [1,5]-hydrogenatom shift to produce (the yet more highly oxidized) benzene (11).

The most highly oxidized Diels-Alder variant is the cycloadditionbetween a 1,3-diyne 12 and an alkynyl diynophile (7), which generateso-benzyne directly. Given the potential generality of this reaction, itis surprising that it has not been highly exploited. However, 4+2cyclizations leading to benzynes have received only limited attention.See for example, K. Miyawaki, et al., Tetrahedron Lett., 1997, 38,3943-3946; A. Bradley and R. Johnson, J. Am. Chem. Soc., 1997, 119,9917-9918; K. Miyawaki, et al., Tetrahedron Lett., 1998, 39, 6923-6926;I. Ueda, et al., Tetrahedron Lett., 1999, 40, 319-322; I. Ueda, et al.,Tetrahedron Lett., 2000, 41, 1447-1451; K. Miyawaki, et al.,Heterocycles., 2000, 54, 887-900; T. Kawano, et al., Tetrahedron Lett.,2005, 46, 1233-1236; T. Kawano, et al., Bull. Chem. Soc, Jpn., 2006, 79,944-949; K. Torikai, et al., Bioorganic and Medicinal Chemistry, 2008,16, 5441-5451; J. Tsui and B. Sterenberg, Organometallics, 2009, 28,4906-4908; R. Johnson, J. Phys. Org. Chem., 2010, 23, 283-292; T.Kitamura, Aust. J. Chem., 2010, 63, 987-1001; and K. Cahill, et al.,Aust. J. Chem., 2010, 63, 1007-1012.

SUMMARY OF THE INVENTION

Applicant has discovered a mild method that allows for the preparationof polycyclic ring systems by the cyclization of poly-yne compounds.Accordingly, in one embodiment the invention provides a methodcomprising, cyclizing a tri-yne compound at a temperature below about300° C. to provide a polycyclic compound.

In one embodiment the invention provides a method comprising, cyclizinga nonaromatic compound comprising at least three alkyne groups at atemperature below about 300° C. to provide a polycyclic compound.

In one embodiment the invention provides a method comprising cyclizing apoly-yne compound of formula I:W—X—Y  (I)at a temperature below about 300° C. to provide a polycyclic compound,wherein:

W is an organic group that comprises two or more alkyne groups;

X is selected from a) a linking group that comprises 2-20 carbon atomsand at least one severable group, or b) a non-aromatic linking groupthat comprises 2-20 carbon atoms; and

Y is an organic group that comprises at least one alkyne group.

Applicant has also discovered a mild method that allows for thepreparation of cyclic systems by the intermolecular cyclization of afirst compound that comprises two or more alkyne groups with a secondcompound that comprises at least one alkyne group. Accordingly, in oneembodiment the invention provides a method comprising, cyclizing a firstcompound that comprises two or more alkyne groups with a second compoundthat comprises at least one alkyne group at a temperature below about300° C. to provide a corresponding cyclic compound. Applicant has alsodiscovered a mild method that allows for the preparation of cyclicsystems by associating a first compound that comprises two or morealkyne groups and a second compound that comprises at least one alkynegroup with a template such that the first compound and the secondcompound are properly aligned to allow for the formation of a cycliccompound from the intermolecular cyclization of at least three alkynegroups from the first compound and the second compound. Accordingly, inone embodiment the invention provides a method comprising, associating afirst compound that comprises two or more alkyne groups and a secondcompound that comprises at least one alkyne group with a template suchthat the first compound and the second compound are properly aligned toallow for the formation of a cyclic compound from the intermolecularcyclization of at least three alkyne groups from the first compound andthe second compound.

In one embodiment the invention provides a method comprising, 1)associating a first compound that comprises two or more alkyne groupsand a second compound that comprises at least one alkyne group with atemplate such that the first compound and the second compound areproperly aligned to allow for the formation of a cyclic compound fromthe intermolecular cyclization of at least three alkyne groups from thefirst compound and the second compound, and 2) allowing at least twoalkyne groups from the first compound and one alkyne of the secondcompound to cyclize to form a first cyclic compound.

The invention also provides compounds and materials prepared accordingto the methods of the invention.

DETAILED DESCRIPTION

In the course of an otherwise unrelated study, an attempt was made toprepare the ketotetrayne 14 by oxidation of the precursor alcohol 13with manganese dioxide (Scheme 3). Surprisingly, the major product fromthis experiment, formed in about 6 hours, was the (hexasubstituted)benzene derivative 15 (53% yield after purification). From this resultit was postulated that the benzyne intermediate 16/16′ was being bothreadily formed and efficiently trapped by the oxygen atom in thefortuitously placed siloxyethyl group. Migration of the silyl group fromO to C within zwitterion 17 would account for formation of 15.

Another specific example is the cyclization of tri-yne 21 to tetracycle22 at ambient temperature and with high yield. The synthesis ofsubstrate 21 is shown in Scheme 4. It is representative of the routesthat are used to prepare many of the substrates shown as examples of theinvention elsewhere in this document. In particular, a Sonogashiracross-coupling of 18 with 19 gives the enediyne 20. Addition of analkynyl anion (here, trimethylsilylethynyllithium) and oxidation of theresulting propargylic alcohol gives the triynone 21. Cyclization of 21occurs in chlorinated hydrocarbon solvents (dichloromethane, chloroform,1,2-dichloroethane, 1,2-dichlorobenzene), acyclic hydrocarbon solvents(heptane, hexane, hexanes, petroleum ether), and aromatic solvents(e.g., toluene or benzene).

Subsequent studies that are described herein have shown i) theefficiency and generality of this cyclization reaction; ii) the easyaccessibility of poly-yne substrates via convergent assembly strategies;and iii) an enticingly wide variety of trapping reactions, includingsome that are unique to the reagent-free conditions used for thesethermal cycloisomerizations. Each of the benzyne-generating and-trapping stages considerably increases product structural complexity,thereby amplifying the overall impact of these tandem transformations.Thus, the cyclization methods of the invention are generally useful forpreparing a wide array of cyclic compounds that are useful as dyes,pesticides, pharmaceuticals, and in the electronics industry, interalia. The methods of the invention can be carried out under mildconditions. Accordingly, they may be particularly useful for preparingcomplicated cyclic ring systems as well as cyclic ring systems thatpossess sensitive functionality.

The following definitions are used, unless otherwise described: halo isfluoro, chloro, bromo, or iodo. Alkyl, alkoxy, etc. denote both straightand branched groups; but reference to an individual radical such aspropyl embraces only the straight chain radical, a branched chain isomersuch as isopropyl being specifically referred to. Aryl denotes a phenylradical or an ortho-fused bicyclic carbocyclic radical having about nineto ten ring atoms in which at least one ring is aromatic. Heteroarylencompasses a radical of a monocyclic aromatic ring containing five orsix ring atoms consisting of carbon and one to four heteroatoms eachselected from the group consisting of non-peroxide oxygen, sulfur, andN(X) wherein X is absent or is H, O, (C₁-C₄)alkyl, phenyl or benzyl, aswell as a radical of an ortho-fused bicyclic heterocycle of about eightto ten ring atoms comprising one to four heteroatoms each selected fromthe group consisting of non-peroxide oxygen, sulfur, and N(X).

Specific values listed below for radicals, substituents, and ranges, arefor illustration only; they do not exclude other defined values or othervalues within defined ranges for the radicals and substituents.

Specifically, (C₁-C₆)alkyl can be methyl, ethyl, propyl, isopropyl,butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, or iso-hexyl;(C₃-C₆)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl; (C₃-C₆)cycloalkyl(C₁-C₆)alkyl can be cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, or2-cyclohexylethyl; (C₁-C₆)alkoxy can be methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, orhexyloxy; (C₁-C₆)alkanoyl can be acetyl, propanoyl or butanoyl;(C₁-C₆)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, orhexyloxycarbonyl; (C₁-C₆)alkylthio can be methylthio, ethylthio,propylthio, isopropylthio, butylthio, isobutylthio, pentylthio, orhexylthio; (C₂-C₆)alkanoyloxy can be acetoxy, propanoyloxy, butanoyloxy,isobutanoyloxy, pentanoyloxy, or hexanoyloxy; aryl can be phenyl,indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl,triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl,pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide),thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or itsN-oxide) or quinolyl (or its N-oxide).

The term “amino acid,” comprises the residues of the natural amino acids(e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile, Leu,Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, as wellas unnatural amino acids (e.g. phosphoserine, phosphothreonine,phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, citruline, α-methyl-alanine, para-benzoylphenylalanine,phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). Theterm also comprises natural and unnatural amino acids bearing aconventional amino protecting group (e.g. acetyl or benzyloxycarbonyl),as well as natural and unnatural amino acids protected at the carboxyterminus (e.g. as a (C₁-C₆)alkyl, phenyl or benzyl ester or amide; or asan α-methylbenzyl amide). Other suitable amino and carboxy protectinggroups are known to those skilled in the art (See for example, T. W.Greene, Protecting Groups In Organic Synthesis; Wiley: New York, 1981,and references cited therein). An amino acid can be linked to theremainder of a compound of formula I through the carboxy terminus, theamino terminus, or through any other convenient point of attachment,such as, for example, through the sulfur of cysteine.

The term saccharide includes monosaccharides, disaccharides,trisaccharides and polysaccharides. The term includes glucose, sucrosefructose and ribose, as well as deoxy sugars such as deoxyribose and thelike. Saccharide derivatives can conveniently be prepared as describedin International Patent Applications Publication Numbers WO 96/34005 and97/03995. A saccharide can conveniently be linked to the remainder of acompound through an ether bond.

The term “peptide” describes a sequence of 2 to 25 amino acids (e.g. asdefined hereinabove) or peptidyl residues. The sequence may be linear orcyclic. For example, a cyclic peptide can be prepared or may result fromthe formation of disulfide bridges between two cysteine residues in asequence. A peptide can be linked to the remainder of a compound offormula I through the carboxy terminus, the amino terminus, or throughany other convenient point of attachment, such as, for example, throughthe sulfur of a cysteine. Preferably a peptide comprises 3 to 25, or 5to 21 amino acids. Peptide derivatives can be prepared as disclosed inU.S. Pat. Nos. 4,612,302; 4,853,371; and 4,684,620, or as described inthe Examples hereinbelow. Peptide sequences specifically recited hereinare written with the amino terminus on the left and the carboxy terminuson the right.

As used herein the term tri-yne includes compounds that have only threealkyne groups. The tri-yne can include any other organicfunctionalities, provided they do not interfere with the cyclizationreactions.

The term “nonaromatic compound” means a poly-yne compound that does notinclude an aromatic group (e.g. an aryl or heteroaryl) in the portion ofthe compound between the di-yne and the alkyne that cyclize with oneanother, according to the methods of the invention. The nonaromaticcompound includes “aromatic-free compounds,” which are poly-ynes that donot comprise any aromatic groups whatsoever.

The term “cyclic” includes both monocyclic and polycyclic systems. Inone embodiment of the invention the term cyclic is a monocyclic ringsystem or compound. In another embodiment of the invention the termcyclic is a polycyclic ring system or compound.

In one embodiment W comprises 2, 3, 4, or 5 alkyne groups.

In one embodiment W comprises 2, or 3 alkyne groups.

In one embodiment X is a linking group that comprises 2-20 carbon atomsand at least one severable group.

In one embodiment X is a linking group that comprises 2-10 carbon atomsand at least one severable group.

In one embodiment the severable group is selected from an ester, anamide, a carbonate, a carbamate, an ether, a silylether, an alkene, aurea, a sulfide, a disulfide, a borate ester, a borinate ester, analuminate ester, a silicate ester, a hydrazine, an azo moiety, asulfone, a phosphate ester, and a phosphonate ester.

In one embodiment X is a non-aromatic linking group that comprises 2-20carbon atoms. It is to be understood that the linking group, in additionto comprising 2-20 carbon atoms, can also optionally comprise one ormore heteroatoms (e.g. O, S, N, or P) or one or more carbonyl groups.

In one embodiment X is a non-aromatic linking group that comprises 2-10carbon atoms. It is to be understood that the linking group, in additionto comprising 2-10 carbon atoms, can also optionally comprise one ormore heteroatoms (e.g. O, S, N, or P) or one or more carbonyl groups.

In one embodiment of the invention X is a divalent, branched orunbranched, saturated or unsaturated, hydrocarbon chain, having from 1to 20 carbon atoms, which chain can optionally be substituted on carbonwith one or more substituents selected from the group consisting of(C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy,(C₁-C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo,hydroxy, oxo, carboxy, aryl, aryloxy, heteroaryl, amino acid, peptide,saccharide, and heteroaryloxy; wherein one or more of the carbon atomsin the chain can optionally be replaced with —O—, -aryl-, heteroaryl, or—N(R)—; each R is independently H or (C₁-C₆)alkyl; and wherein any arylis optionally substituted with one or more (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl, cyano,nitro, halo, or hydroxy.

In one embodiment of the invention X is a divalent, branched orunbranched, saturated or unsaturated, hydrocarbon chain, having from 1to 20 carbon atoms, wherein one or more of the carbon atoms isoptionally replaced by (—O—) or (—NR—), and wherein the chain isoptionally substituted on carbon with one or more oxo substituents.

In one embodiment of the invention X is a divalent, branched orunbranched, saturated or unsaturated, hydrocarbon chain, having from 3to 15 carbon atoms, wherein one or more of the carbon atoms isoptionally replaced by (—O—) or (—NR—), and wherein the chain isoptionally substituted on carbon with one or more substituents selectedfrom the group consisting of (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl,(C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁-C₆)alkoxycarbonyl,(C₁-C₆)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo, carboxy,aryl, aryloxy, heteroaryl, amino acid, peptide, saccharide, andheteroaryloxy.

In one embodiment of the invention X is a divalent, branched orunbranched, saturated or unsaturated, hydrocarbon chain, having from 3to 15 carbon atoms, wherein one or more of the carbon atoms isoptionally replaced by (—O—) or (—NR—), and wherein the chain isoptionally substituted on carbon with one or more oxo substituents.

In one embodiment of the invention X is a divalent, branched orunbranched, saturated or unsaturated, hydrocarbon chain, having from 3to 15 carbon atoms, wherein the chain is optionally substituted oncarbon with one or more oxo substituents.

In one embodiment of the invention X is a divalent, branched orunbranched, hydrocarbon chain, having from 4 to 8 carbon atoms, whereinthe chain is optionally substituted on carbon with one or more oxosubstituents.

In one embodiment of the invention X is a peptide.

In one embodiment of the invention X is an amino acid.

In one embodiment of the invention X is a saccharide. In one embodimentof the invention X is a monosaccharide. In one embodiment of theinvention X is a disaccharide.

In one embodiment of the invention X comprises a monocyclic or bicyclicaryl or heteroaryl ring.

In one embodiment of the invention X comprises a monocyclic aryl ormonocyclic heteroaryl ring.

In one embodiment of the invention X is a comprises a phenyl ring.

In one embodiment of the invention X is:

wherein Z is a monocyclic or bicyclic aryl or bicyclic heteroaryl ring.In one embodiment of the invention Z is a monocyclic aryl or monocyclicheteroaryl ring.

In one embodiment of the invention X is:

In one embodiment of the invention X is:

In one embodiment Y comprises 1, 2, 3, or 4 alkyne groups.

In one embodiment Y comprises 1 or 2 alkyne groups.

In one embodiment Y has only 1 or 2 alkyne groups.

Benzyne Trapping Reagents

The methods of the invention can also further comprise trapping thebenzyne intermediates formed by cyclization with a suitable benzynetrapping reagent. This trapping can be used to terminate the cyclizationreaction and form the final product, for example, by adding hydrogen tothe benzyne intermediate, or this trapping can be used to furtherelaborate the benzyne intermediate to provide a final product, forexample, by incorporating all or a portion of a trapping molecule intothe final product. A number of benzyne trapping reagents are known inthe field of organic chemistry; for example, see T. Kitamura, Aust. J.Chem., 2010, 63, 987-1001. Hoffmann, R. W. Organic Chemistry, A Seriesof Monographs—Volume 11, Academic Press, New York, 1967.

In one embodiment of the invention, the benzyne trapping reagent is anaromatic agent like phenol, furan, 2H-pyrone, benzene, naphthalene,anthracene, phenanthrene, tetracene, pentacene, 6-memberedheteroaromatic compounds containing one to four nitrogen atoms(pyridine, pyridazine, pyrazine, pyrimidine, triazines, tetrazines),fused bicyclic heteroaromatic compounds containing 1-4 nitrogen atoms(quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, indole,isoindole, benzofuran, isobenzofuran) and their substituted derivatives.

In one embodiment of the invention, the benzyne trapping reagent is aformal hydrogen molecule (H₂) donor like a cyclic hydrocarbon (e.g.,cyclopentane, indane, taxadiene, cyclooctane, or cycloheptane), a cyclicether (e.g., tetrahydrofuran or p-dioxane), or a cyclic amine (e.g.,N-methylpiperidine, quinuclidine, or 1,4-diaza[2.2.2]bicyclooctane).

In one embodiment of the invention, the benzyne trapping reagent is anoxygen-based nucleophile of protic [phenol, alcohol, carboxylic acid,amide, carbamate, hydrogen peroxide, alkyl hydroperoxide, peroxyacid (ortheir anionic conjugate bases)] or aprotic [ether, dialkyl peroxide,acyl alkyl peroxide, diacylperoxide] nature.

In one embodiment of the invention, the benzyne trapping reagent is asulfur containing nucleophile like a thiol, sulfide, thioester,thioacid, sulfenic acid, sulfinic acid (or their anionic conjugatebases) sulfenic ester, or sulfinic ester; a sulfur containingnucleophile like a thiol, sulfide, thioester, thioacid, sulfenic acid,sulfinic acid (or their anionic conjugate bases) sulfenic ester,sulfinic ester, disulfides, thiosulfonates.

In one embodiment of the invention, the benzyne trapping reagent is aselenium-containing reagent like a selenol, selenide, or diselenide.

In one embodiment of the invention, the benzyne trapping reagent is aphosphorous-containing nucleophile like a phosphine, a phosphite, aphosphoramide, a phosphoramidate, or a phosphinamide.

In one embodiment of the invention, the benzyne trapping reagent is anitrogen-containing nucleophile like ammonia, a primary amine, asecondary amine, a tertiary amine, an amide, a carbamate, an imide, animine, a hydrazine, a hydrazide, a hydrazone, an azo compound, anisonitrile, a nitrile, or cyanide ion.

In one embodiment of the invention, the benzyne trapping reagent is ahalogen source like an ammonium salt of a fluoride, chloride, bromide,or iodide ion.

In one embodiment of the invention, the benzyne trapping reagent is ametal halide salt like LiX, NaX, KX, ZnX₂, MgX₂, KBF₄, BX₃, AlX₃, CeX₃,GaX₃, InX₃, SiX₄, SmX₃, SnX₄, SnX₂, XeF₂, CuX, CuX₂, NiX₂, FeX₂, PdX₂,CoX₂, RuX₃, TiX₄, TiX₃, or FeX₃.

In one embodiment of the invention, the benzyne trapping reagent is anucleophilic initiator and ≧one molar equivalent of an electrophilicpartner: e.g., the nucleophile could be a halide, alkoxide, aryloxide,thiolate, carboxylate, amine, amide, cyanide, sulfinate, and theelectrophile could be an acid chloride, a carboxylic acid, a Bronstedacid, a carboxylic ester, an acylcyanide, an alkoxycarbonyl anisocyanate, a borate ester, a boronate ester, a borinate ester, analuminate ester, a silicate ester, a halosilane, a silyltriflate, or anelectrophilic halogenating agent like X₂, an N-halosuccinimide,Selectfluor®, a trihalide ion, 2,4,4,6-tetrahalocyclohexadienone, orpolyhalogenated alkane or ketone.

In one embodiment of the invention, the benzyne trapping reagent is ahydrogen halide, a halosilane, or an alkyl halide.

In one embodiment of the invention, the benzyne trapping reagent is api-bond cycloaddend like carbon disulfide (CS₂), carbon dioxide (CO₂),carbonyl sulfide (CSO), an isocyanate, an isothiocyanate, acarbodiimide, a strained alkene, a strained alkyne, a vinylether, anenamine, an acrylate, an indole, an isoindole, a benzofuran, or a1,3-dipole reagent (e.g., an alkyl or aryl azide, a nitrone, a nitrileoxide, a pyridine N-oxide, or an azomethine imine).

In one embodiment of the invention, the benzyne trapping reagent is aphenol, a furan, cyclooctane, cycloheptane, an alcohol (e.g. aC₁-C₆alcohol), or benzene.

In one embodiment of the invention, the benzyne trapping reagent is aphenol, a furan, cyclooctane, cycloheptane, or benzene.

In one embodiment of the invention, the benzyne trapping reagent is anaromatic agent, a formal hydrogen molecule (H₂) donor, an oxygen-basednucleophile of protic or aprotic nature, a sulfur containingnucleophile, a selenium-containing nucleophile, a phosphorous-containingnucleophile, a nitrogen-containing nucleophile, a halogen source, ametal halide salt, a hydrogen halide, an ammonium halide, a halosilane,an alkyl halide, or a pi-bond cycloaddend.

In one embodiment of the invention, the benzyne trapping reagent is anaromatic agent, a formal hydrogen molecule (H₂) donor, an oxygen-basednucleophile of protic or aprotic nature, a sulfur containingnucleophile, a selenium-containing nucleophile, a phosphorous-containingnucleophile, a nitrogen-containing nucleophile, a halogen source, ametal halide salt, a hydrogen halide, a halosilane, an alkyl halide, ora pi-bond cycloaddend.

Severable Groups

In one embodiment of the invention, the di-yne portion and the mono-yneof the material to be cyclized can be linked by a linking group thatincludes one or more severable groups. Following cyclization, theseseveral groups can be maintained in the polycyclic product, such thatthe linking group forms a ring in the polycyclic product, or theseverable group can be severed (e.g. hydrolyzed) to open the ring formedby the linking group. Any suitable group can be incorporated into thelinking group, provided the group does not interfere with thecyclization reaction.

In one embodiment of the invention, the severable group is selected froman ester, an amide, a carbonate, a carbamate, an ether, a silylether, analkene, a urea, a sulfide, a disulfide, a borate ester, a borinateester, an aluminate ester, a silicate ester, a hydrazine, an azo moiety,a sulfone, a phosphate ester, and a phosphonate ester.

Templated Reactions

In one embodiment of the invention the compound that comprises two ormore alkyne groups (the first compound) and the compound that comprisesat least one alkyne group (the second compound) can be associated with atemplate that helps align the di-yne and the mono-yne groups andfacilitate the intermolecular cyclization reaction.

The compounds can be associated with the template through any suitablemeans. For example, in one embodiment of the invention, the firstcompound and the second compound are associated with the template bydipole-dipole interactions or by van der Waals forces; in anotherembodiment of the invention, the first compound and the second compoundare associated with the template by coordination; in another embodimentof the invention, the first compound and the second compound areassociated with the template by hydrogen bonds; in another embodiment ofthe invention, the first compound and the second compound are eachterminally substituted with a group that is capable of associating withthe template (e.g. an amino nitrogen, a thiol, an alcohol, or acarboxylic acid).

In one embodiment the template is a metal, an inorganic molecule, anorganic molecule, or a solid support. In one embodiment the template isan aluminum atom, a boron atom, a silicon atom, a titanium atom, aphosphorous atom, or a divalent metal atom (e.g. Mg++, Ca++, Zn++, Ni++,or Fe++).

In one embodiment two alkyne groups of the first compound are alignedwithin about 2.8 to about 5.2 Angstroms of an alkyne group on the secondcompound to allow for said alkyne groups to cyclize.

Starting Materials

The starting polyalkynes used in the methods of the invention can beprepared using methods known in the field of organic chemistry, or theycan be prepared using methods similar to those described in thefollowing Schemes 5-8, wherein R, R¹, and R² represent any suitableorganic group that will not significantly interfere with the cyclizationreaction.

Schemes 5-8. Complementary, general strategies for the efficient andconvergent synthesis of starting materials.General Experimental Procedure for Each of the Key Classes of ReactionsUsed to Prepare the Starting MaterialsGeneral Procedure for Cadiot-Chodkiewicz Cross-Coupling of Two Alkynes.

CuCl (0.1-0.2 equiv) was added to a solution of the terminal alkyne (1equiv) and the 1-bromoalkyne (1.1 equiv) in freshly deaerated piperidine(0.2-1.0 M) at 0° C. with stirring. After 1 hour the resulting mixturewas partitioned between EtOAc and satd. aq. NH₄Cl. The aqueous phase wasextracted with EtOAc and the combined organic extracts were washed withbrine, dried over MgSO₄, and concentrated. Purification by MPLC or flashchromatography gave the cross-coupled conjugated diyne.

General Procedure for MnO₂ Oxidation

MnO₂ (25 equiv) was added to a solution of the ynol (1 equiv) in CH₂Cl₂(0.3 M). This black heterogeneous mixture was vigorously stirred at roomtemperature. After 16 hours the reaction mixture was filtered through aplug of Celite (EtOAc eluent). Purification by either MPLC or flashchromatography gave the ynone product.

General Procedure for Glaser Coupling of Terminal Alkynes

As adapted from a procedure reported by Lei (Org. Lett., 2009, 11,709-712), CuI (0.05 equiv) and NiCl₂ (anhydrous, 0.05 equiv) were addedto a solution of TMEDA (0.2 equiv) in THF. The resulting suspension wasstirred for 2 minutes at room temperature. Terminal alkyne 1 (1 equiv)and terminal alkyne 2 (varying amounts, depending upon the preciousness)were added sequentially, and the resulting mixture was stirred under aheadspace of air for 12 hours at room temperature. The resulting mixturewas partitioned between EtOAc and satd. aq. NH₄Cl. The aqueous layer wasextracted with EtOAc. The combined organic layers were washed withbrine, dried with Na₂SO₄, and concentrated. The residue was purified byflash chromatography or MPLC to provide the desired cross coupledconjugated diyne.

General Procedure Alkyne Bromination:

NBS (1.1 equiv) and AgNO₃ (0.1 equiv) were added to a solution ofterminal alkyne (1 equiv) in acetone (0.2 M) at room temperature. Theflask was wrapped in aluminum foil and stirred for 2 hours. Water wasadded and the aqueous phase extracted 3× with EtOAc. The combinedorganic extracts were washed with brine, dried over MgSO₄, andconcentrated. Purification by MPLC or flash chromatography gave the1-bromoalkyne.

Reaction Conditions

The cyclization reactions can be carried out at any suitabletemperature. Typically, the cyclization reactions are carried out at atemperature below about 300° C. In one embodiment of the invention, thecyclization reactions are carried out at a temperature below about 200°C.; in one embodiment of the invention, the cyclization reactions arecarried out at a temperature below about 150° C.; in another embodimentof the invention the cyclization reactions are carried out at atemperature below about 100° C.; in another embodiment of the inventionthe cyclization reactions are carried out at a temperature below about80° C.; in another embodiment of the invention the cyclization reactionsare carried out at a temperature below about 50° C.; and in anotherembodiment of the invention the cyclization reactions are carried out ata temperature below about 30° C. In one embodiment of the invention thecyclization reactions are carried out at a temperature above about 0°C.; in another embodiment of the invention the cyclization reactions arecarried out at a temperature above about 20° C.

In one embodiment, the methods of the invention are carried out in theabsence of a transition metal catalyst. As used herein, the phrase “inthe absence of a transition metal catalyst” means that the cyclizationreaction is not catalyzed to any significant degree by a transitionmetal. In another embodiment, the methods of the invention are carriedout in the absence of any metals (e.g. transition metals andnon-transition metals).

The cyclization reactions of the invention can be carried out neat, orthey can be carried out in the presence of a suitable solvent. Anysuitable solvent, or combination of solvents can be used. For example,the reactions can be carried out in a suitable organic solvent.Typically, the reactions are carried out in aprotic solvents, includinghydrocarbons, ethers, halocarbons, and aromatic solvents. The reactionscan also be carried out in the presence of protic solvents, such aswater and alcohols (e.g. methanol of tert-butanol). For example, thereactions can be carried out in hexanes, heptane, octane, chloroform(including CDCl3), dichloromethane, benzene, furan, toluene, phenol,cyclooctane, cycloheptane, cyclohexane, tetrahydrofuran,N,N-dimethylformamide, methyliodide, methanol, water, or ethylpropanoate, or mixtures thereof. In one embodiment of the invention, thesolvent can include a benzyne trapping reagent, such as benzene, furan,toluene, phenol, cyclooctane, cycloheptane, or methyliodide.

Applications

The methods of the invention are useful for preparing a wide variety ofcyclic compounds that may find use as dyes, pesticides, orpharmaceuticals, or in the electronics industry, inter alia. Forexample, the methods of the invention could be used to preparepolycyclic intermediates that could be converted to the followingnatural products (II-A to II-D) or pharmaceuticals (II-E and II-F), asillustrated in Schemes 9-14.

Salfredins B₁₁ (230), A₄ (236), and C₁ (II-A) (isolated from Crucibulumsp.) are aldose reductase inhibitors, a class of agents being developedfor treatment of diabetic retinopathy and neuropathy. A cyclizationreaction of the invention can be used to prepare such compounds asillustrated in Scheme 9. Cyclization of substrates 227 and 233 (viaalcohol trapping within 228 and 234) will give 229 and 235. Precedentedoxidations [and N-alkylation (K₂CO₃, BrCH₂CO₂H) en route to 236] willgive the targets 230, 236, and II-A in 2, 4, and 3 steps, respectively.

Beilschmiedic acid G (II-B) is a member of a family of antibacterialagents reported in 2011. It was isolated in Cameroon from the bark ofBeilschmiedia anacardioides, which is known for its ancient use as atreatment for uterine cancer and infection, and is thought to bebiogenetically related to the co-existing endiandric acids. Acyclization reaction of the invention can be used to prepare such acompound as illustrated in Scheme 10.

Artonol B (II-C) is cytotoxic against several tumor cell lines. Acyclization reaction of the invention can be used to construct the D-and C-rings in II-C via cyclization of 243 and trapping by theC4a-oxygen as illustrated in Scheme 11. Oxidation of the reactivebenzylic (captodatively activated) methylene groups in 245b (directlyfrom 243b or from acetylation of 245c or 245d) with a Collins or Salmondreagent followed by removal of the MEM will provide artonol B (II-C).

Landomycinone (II-D) is the aglycone core of the angucyclin antibiotics.A cyclization reaction of the invention can be used to prepare such acompound as illustrated in Scheme 12. Diyne 246 can be preparedfollowing the protocol of Vollhardt for analogous diynes from3-hydroxyphthalide. Bromoalkyne 247b can be made from known 247a.Cross-coupling of the bis-propargylic alcohol 246 with 247 followed bydiol oxidation gives the diketone 248. The key C—C-bond forming eventwithin the highly electrophilic benzyne 249 is a silylphenol-eneaddition. Synthesis of II-D can be completed by thermal retro-DAextrusion of CpH, B-ring oxidation in 250, and O-TBS cleavage.Successful reduction of this phenolic-ene strategy to practice wouldrepresent a non-trivial advance in efficiency vis-à-vis the two existingroutes to II-D. It would also pave the way for use of this tactic forother related families of highly oxygenated polycyclic natural productsof contemporary biological import (e.g., kibdelones and pradimicin).

Carteolol (Cartrol®, II-E) and several structurally relatedaryloxypropanolamines are α-adrenergic blocking agents that have longplayed an important role in the management of a wide variety of humancardiovascular ailments. A cyclization reaction of the invention can beused to prepare such compounds as illustrated in Scheme 13. Acyclization reaction of the invention can also be used to prepare theketone- and diol-containing β-blockers Betagan® (255) and Corgard®(257).

A cyclization reaction of the invention can also be used to prepareCellCept® (II-F) as illustrated in Scheme 14. First introduced in 1995by Hoffmann La-Roche, CellCept® (II-F) is an immunosuppressant agentwidely used by organ transplant patients. It is currently in multipleclinical trials for a wide variety of additional indications. Worldwideannual sales of CellCept® often exceed $1B.

The invention will now be illustrated by the following non-limitingExamples.

EXAMPLES

The following reactions that illustrate the methods of the inventionwere carried out under the conditions shown.

Example 1

Spectral Data for Product of Example 11,2-Bis(trimethylsilyl)-9H-fluoren-9-one

¹H NMR (500 MHz, CDCl₃): δ=7.72 (d, J=7.51 Hz, 1H), 7.60 (ddd, J=1.0,1.0, 7.3 Hz, 1H), 7.50 (ddd, J=1.0, 1.0, 7.4, 1H), 7.46 (ddd, J=1.2,7.3, 7.3 Hz, 1H), 7.45 (d, J=7.5 Hz, 1H), 7.28 (ddd, 1.3, 7.3, 7.3 Hz,1H), 0.44 [s, Si(CH₃)₃], and 0.39 [s, Si(CH₃)₃]. GC-MS t_(r)=11.44 min;m/z: 324, 309, 251, 147, and 73.

Example 2

Spectral Data for Product of Example 23-Chloro-1,2-bis(trimethylsilyl)-9H-fluoren-9-one

¹H NMR (500 MHz, CDCl₃): δ=8.17, (ddd, J=0.9, 0.9, 7.6 Hz, 1H), 7.65(ddd, J=1.0, 1.1, 7.3 Hz, 1H), 7.61 (s, 1H), 7.52 (ddd, J=1.2, 7.6, 7.6Hz, 1H), 7.34 (ddd, J=1.0, 7.5, 7.5 Hz, 1H), 0.42 [s, Si(CH₃)₃], and0.40 [s, Si(CH₃)₃]. GC-MS t_(r)=11.91 min; m/z: 345, 343, 287, 250, 164,and 73.

Example 3

Spectral Data for Product of Example 33-(tert-Butoxy)-1,2-bis(trimethylsilyl)-9H-fluoren-9-one

¹H NMR (500 MHz, CDCl₃): δ=7.55 (ddd, J=1.0, 1.0, 7.3 Hz, 1H), 7.42 (d,J=1.1 Hz, 1H), 7.42 (dd, J=1.1, 1.1 Hz, 1H), 7.26 (nfom, 2H), 7.04 (s,1H), 1.61 [s, C(CH₃)₃], 0.40 [s, Si(CH₃)₃], and 0.35 [s, Si(CH₃)₃]. ¹³CNMR (125 MHz, CDCl₃): δ=194.4, 166.9, 155.1, 146.8, 143.4, 141.7, 135.3,133.9, 133.8, 129.3, 123.6, 119.5, 107.2, 79.9, 29.3, 3.2, and 2.9.GC-MS t_(r)=12.55 min; m/z: 396, 340, 325, 309, 279, 267, 250, 235, 73,and 57.

Example 4

Spectral Data for Product of Example 44,5-Bis(trimethylsilyl)-3,3a-dihydro-2H-fluoreno[3′,4′:3,4]cyclobuta[1,2-b]furan-6(10dH)-one

GC-MS t_(r)=14.50 min; m/z: 392, 377, 349, 319, 303, 289, 275, 215, and73.

Example 5

Spectral Data for Product of Example 59-Oxo-1,2-bis(trimethylsilyl)-9H-fluorene-3-carbonitrile

¹H NMR (500 MHz, CDCl₃): δ=7.72 (s, 1H), 7.66 (ddd, J=1.0, 1.0, 7.4 Hz,1H), 7.55 (nfom, 1H), 7.54 (nfom, 1H) 7.37, (nfom), 0.54 [s, Si(CH₃)₃],and 0.42 [s, Si(CH₃)₃]. ¹³C NMR (125 MHz, CDCl₃): δ=195.0, 157.4, 153.9,143.3, 143.0, 142.6, 135.3, 133.6, 130.3, 124.6, 124.4, 123.3, 120.8,120.3, 2.8, and 2.4. GC-MS t_(r)=13.63 min; m/z: 349, 334, 318, 276,260, 159, and 73.

Example 6

Spectral Data for the Products of Example 64-(Trimethylsilyl)-2H-fluoreno[3,2-b]furan-5(3H)-one and10-Propionyl-4-(trimethylsilyl)-2H-fluoreno[3,2-b]furan-5(3H)-one

Spectral data for proton-trapped product: ¹H NMR (500 MHz, CDCl₃):δ=7.53 (dd, J=7.3 0.7 Hz, ArHCC═O), 7.42 (ddd, J=7.3, 7.3, 1.0 Hz, ArH),7.39 (dd, J=6.2, 0.9 Hz, ArH) 7.25 (ddd, J=7.2, 7.2, 1.3 Hz, ArH), 6.92(s, ArHCOCH₂), 4.63 (t, J=8.5 Hz, CH₂O), and 3.27 (t, J=8.5 Hz,CH₂CH₂O), and 0.40 [s, Si(CH₃)₃]. HR ESI-MS: C₁₈H₁₈O₂Si [M+Na]⁺ requires317.0968. found 317.0980. Spectral Data for propionate-trapped product:¹H NMR (500 MHz, CDCl₃): δ=7.55 (d, J=7.0 Hz, ArHCC═O), 7.38-7.43 (m,1H), 7.35, (ddd, J=7.6, 7.6, 1.2 Hz, 1H), 7.23 (dd, J=6.9, 0.9, 0.9 Hz,1H), 4.66 (t, J=8.8, CH₂CH₂OC), 3.29 (t, J=8.5 Hz, CH₂CH₂OC), 2.98 (q,J=7.2 Hz, CH₂CH₃), 1.26 (t, J=7.2 Hz, CH₂CH₃) and 0.40 [Si(CH₃)₃]. GC-MSt_(r)=13.17 min; m/z: 350, 335, 317, 278, 235, 220, 189, and 153.

Example 7

Spectral Data for the Product of Example 74-(Trimethylsilyl)-2H-fluoreno[3,2-b]furan-5(3H)-one

¹H NMR (500 MHz, CDCl₃): δ=7.53 (dd, J=7.3 0.7 Hz, ArHCC═O), 7.38-7.44(m, 2H), 7.25 (ddd, J=7.2, 7.2, 1.3 Hz, ArH), 6.92 (s, ArHCOCH₂), 4.63(t, J=8.8 Hz, CH₂O), and 3.27 (t, J=8.8 Hz, CH₂CH₂O), and 0.40 [s,Si(CH₃)₃]. HR ESI-MS: C₁₈H₁₈O₂Si [M+Na]⁺ requires 317.0968. found317.0980.

Example 8

Spectral Data for the Product of Example 82-(3-Chloropropyl)-3-iodo-1-(trimethylsilyl)-9H-fluoren-9-one

¹H NMR (500 MHz, CDCl₃): δ 8.08 (s, CHCl), 7.60 (d, J=7.3 Hz, CHCC═O),7.47 (ddd, J=7.4, 6.7, 1.1 Hz, ArH), 7.30 (dd, J=7.3, 7.3 Hz, ArH), 3.64(t, J=6.7 Hz, CH₂CH₂CH₂Cl), 3.18 (bt, J=8.3 Hz, CH₂CH₂CH₂Cl), 1.95 (bp,J=6.7 Hz, CH₂CH₂CH₂Cl), and 0.50 [s, Si(CH₃)₃]. HR ESI-MS: C₁₉H₂₀ClIOSi[M+Na]⁺ requires 476.9909. found 476.9960. GC-MS t_(r)=14.03 min; m/z:454, 439, 403, 275, 261, 235, 217, 189, 163, and 73.

Example 9

Spectral Data for the Product of Example 92-(3-Chloropropyl)-3-iodo-1-(trimethylsilyl)-9H-fluoren-9-one

GC-MS t_(r)=14.03 min; m/z: 454, 439, 403, 275, 261, 235, 217, 189, 163,and 73. GC-MS t_(r)=12.24 min; m/z: 328, 313, 277, 250, 235, 221, 203,189, 165, 139, and 73.

Example 10

Spectral Data for the Product of Example 102-(3-Chloropropyl)-3-iodo-1-(trimethylsilyl)-9H-fluoren-9-one

¹H NMR (500 MHz, CDCl₃): δ=8.08 (s, CHCl), 7.60 (d, J=7.3 Hz, CHCC═O),7.47 (ddd, J=7.4, 6.7, 1.1 Hz, ArH), 7.30 (dd, J=7.3, 7.3 Hz, ArH), 3.64(t, J=6.7 Hz, CH₂CH₂CH₂Cl), 3.18 (bt, J=8.3 Hz, CH₂CH₂CH₂Cl), 1.95 (bp,J=6.7 Hz, CH₂CH₂CH₂Cl), and 0.50 [s, Si(CH₃)₃]. GC-MS t_(r)=14.03 min;m/z: 454, 439, 403, 275, 261, 235, 217, 189, 163, and 73.

Example 11

Spectral Data for the Product of Example 115,6,9,10-Tetrakis(trimethylsilyl)-1,2,3,4,7,7a,7b,8,11,12,13,14,16,16a,16b,17-hexadecahydro-7,17:8,16-diepoxybiphenyleno[2,3-a:7,6-a′]difluorene-15,18-dione

¹H NMR (500 MHz, CDCl₃): δ=4.73 (dd, J=3.5, 1.0 Hz, 1H), 4.24 (d, J=3.5Hz, 1H), 3.00 (t, J=2.5 Hz, 1H), 2.48 (nfom, C═C(CH₂)—C═O), 2.28 (nfom,CH₂C═C—C═O), 2.22 (dd, J=3.5, 2.5 Hz, 1H), 1.77 (m, CH₂CH₂CH₂CH₂), 1.69(m, CH₂CH₂CH₂CH₂), 0.23 (s, Si(CH₃)₃), and 0.07 (s, Si(CH₃)₃). LC-MS:t_(r)=4.10; [M+Na]⁺: 811.0

Example 12

Spectral Data for the Product of Example 128-(tert-Butyldimethylsilyl)-4-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-6-tosyl-3,5,6,7-tetrahydro-2H-furo[2,3-f]isoindole

¹H NMR (500 MHz, CDCl₃): δ=7.74 (d, J=8.0 Hz, Ar—H), 7.30 (d, J=8.0 Hz,Ar—H), 4.56 (s, 2H), 4.53 (s, 2H), 4.45 (t, J=8.5 Hz, ArOCH₂), 3.80 (t,J=7.0 Hz, OCH₂CH₂—C), 3.11 (t, J=8.5 Hz, ArCH₂CH₂O), 2.66 (t, J=7.0 Hz,OCH₂CH₂—C), 2.40 (s, Ar—CH₃), 0.92 (s, C(CH₃)₃), 0.82 (s, C(CH₃)₃), 0.27(s, tBuSi(CH₃)₂), 0.10 (s, tBuSi(CH₃)₂). LC-MS: t_(r)=9.31 min; [M+H]⁺:612.1

Example 13

Spectral Data for Product of Example 138-(Triethylsilyl)-4-(4-((triethylsilyl)oxy)but-1-yn-1-yl)-6-tosyl-3,5,6,7-tetrahydro-2H-furo[2,3-f]isoindole

¹H NMR (500 MHz, CDCl₃): δ=7.76 (d, J=8.0 Hz, Ar—H), 7.31 (d, J=8.0 Hz,Ar—H), 4.55 (s, 2H), 4.53 (s, 2H), 4.47 (t, J=8.5 Hz, ArOCH₂), 3.80 (t,J=7.0 Hz, OCH₂CH₂—C), 3.11 (t, J=8.5 Hz, ArCH₂CH₂O), 2.67 (t, J=7.0 Hz,OCH₂CH₂—C), 2.40 (s, Ar—CH₃), 0.99 (t, J=8.0 Hz, Si—CH₂CH₃), 0.87 (t,J=8.0 Hz, Si—CH₂CH₃), 0.78 (t, J=8.0 Hz, Si—CH₂CH₃), 0.64 (t, J=8.0 Hz,Si—CH₂CH₃),

Example 14

Spectral Data for the Product of Example 148-(Triisopropylsilyl)-4-(4-((triisopropylsilyl)oxy)but-1-yn-1-yl)-6-tosyl-3,5,6,7-tetrahydro-2H-furo[2,3-]isoindole

¹H NMR (500 MHz, CDCl₃): δ=7.75 (d, J=8.0 Hz, Ar—H), 7.29 (d, J=8.0 Hz,Ar—H), 4.65 (s, 2H), 4.53 (s, 2H), 4.42 (t, J=8.5 Hz, ArOCH₂), 3.87 (t,J=7.0 Hz, OCH₂CH₂—C), 3.10 (t, J=8.5 Hz, ArCH₂CH₂O), 2.69 (t, J=7.0 Hz,OCH₂CH₂—C), 2.40 (s, Ar—CH₃), 1.45 (septet, CHMe₂), 1.10 (s, CH(CH₃)₂),1.05 (s, CH(CH₃)₂). LC-MS: t_(r)=19.24 min; [M+H]⁺: 696.1

Example 15

Spectral Data for the Product of Example 158-(tert-Butyldimethylsilyl)-2,3,6,7-tetrahydro-6-phenylfuro[2,3-f]isoindol-5-one

¹H NMR (500 MHz, CDCl₃): δ=7.85 (s, Ar—H), 7.84 (s, Ar—H), 7.71 (s,Ar—H), 7.42 (d, J=7.5 Hz, Ar—H), 7.42 (d, J=7.5 Hz, Ar—H), 7.15 (td,J=7.5, 1.0 Hz, Ar—H), 4.76 (s, ArCH₂N), 4.60 (t, J=9.0 Hz, OCH₂), 3.25(t, J=9.0 Hz, ArCH₂CH₂O), 0.92 (s, C(CH₃)₃), 0.42 (s, tBuSi(CH₃)₂.LC-MS: t_(r)=3.40 min; [M+NH₄]⁺: 383.2

Example 16

Spectral Data for Products of Example 16(E)-4-(Pent-1-en-1-yl)-11-(trimethylsilyl)-3,4-dihydroindeno[1,2-g]isochromen-10(1H)-one

¹H NMR (500 MHz, CDCl₃): δ=7.58 (ddd, J=1.0, 1.0, 7.3 Hz, 1H), 7.46(nfom), 7.45 (nfom), 7.37 (d, J=0.8 Hz, 1H), 7.26 (nfom), 5.73 (dddd,J=0.8, 6.8, 6.8, 15.3 Hz, 1H), 5.46 (dddd, J=1.4, 1.4, 8.8, 15.2 Hz,1H), 4.88 (d, J=1.3 Hz, 2H), 3.97 (dd, J=5.3, 11.1 Hz, 1H) 3.66 (dd,J=7.1, 11.1 Hz, 1H), 3.55 (nfom, 1H), 2.09 (ddd, 1.5, 7.0, 7.0 Hz, 1H),2.07 (ddd, J=1.5, 6.8, 6.8 Hz, 1H), 1.46 (sextet, J=7.4 Hz, 2H), 0.95(t, J=7.4 Hz, 3H), and 0.42 [s, Si(CH₃)₃]. GC/MS t_(r)=13.59 min; m/z:376, 361, 331, 306, 287, 202, 189, 137, and 73.(Z)-4-(Pent-1-en-1-yl)-11-(trimethylsilyl)-3,4-dihydroindeno[1,2-g]isochromen-10(1H)-one:¹H NMR (500 MHz, CDCl₃): δ=7.58 (ddd, J=1.0, 1.0, 7.3 Hz, 1H), 7.45(nfom), 7.44 (nfom), 7.32 (d, J=0.7 Hz, 1H), 7.26 (nfom), 5.71 (dddd,J=0.8, 7.5, 7.5, 10.8 Hz, 1H), 5.38 (dddd, J=1.7, 1.7, 9.3, 10.8 Hz,1H), 4.93 (d, J=15.1 Hz, 1H), 4.87 (dd, J=1.28 Hz, 1H), 3.99 (nfom),3.53 (nfom), 2.26 (??, 1H), 1.53 (??, 1H), 1.02 (t, J=7.4 Hz, 3H), and0.42 [s, Si(CH₃)₃]. GC-MS t_(r)=13.68 min; m/z: 376, 361, 331, 287, 215,202, and 73.

Example 17

Spectral Data for Product of Example 174-(Prop-1-en-2-yl)-11-(trimethylsilyl)-3,4-dihydroindeno[1,2-g]isochromen-10(1H)-one

¹H NMR (500 MHz, CDCl₃): δ=7.59 (ddd, J=1.0, 1.0, 7.3 Hz, 1H), 7.48(ddd, J=0.9, 1.6, 7.5 Hz, 1H), 7.45 (ddd, J=1.2, 7.4, 7.4 Hz, 1H) 7.33(d, J=0.7 Hz, 1H), 7.26 (ddd, J=1.5, 7.2, 7.2 Hz, 1H), 5.03 (dq, J=2.1,1.5 Hz, 1H), 4.91 (dq, J=0.8, 2.9 Hz, 1H), 4.90 (dd, J=1.2, 15.2 Hz,1H), 4.85 (dd, J=1.3, 15.2 Hz, 1H), 3.97 (dd, J=5.5, 11.3 Hz, 1H), 3.84(dd, J=6.0, 11.3 Hz, 1H), 3.63 (ddq, J=5.7, 5.7, 0.8 Hz, 1H), 1.72 (dd,J=0.9, 1.5 Hz, CCH₃), and 0.43 [s, Si(CH₃)₃]. ¹³C NMR (125 MHz, CDCl₃):δ=195.1, 145.9, 144.0, 143.1, 142.2, 140.5, 134.6, 134.2, 128.9, 124.0,122.1, 119.8, 155.5, 71.2, 68.3, 47.8, 20.3, and 2.7. IR (neat): 2974,2933, 2913, 2853, 2212, 1673, 1630, 1443, 1378, 1352, 1077, 1027, 1002,925, and 897 cm⁻¹. GC-MS t_(r)=12.7 min; m/z: 348, 333, 303, 287, 277,229, 215, 202, 189, 136, and 73. TLC: R_(f) 0.4 (9:1 Hex/EtOAc)

Example 18

Spectral Data for Products of Example 18(E)-4-(2-Chlorovinyl)-11-(trimethylsilyl)-3,4-dihydroindeno[1,2-g]isochromen-10(1H)-one

¹H NMR (500 MHz, CDCl₃): δ=7.30 (ddd, J=0.9, 0.9, 7.4 Hz, 1H), 7.50(nfom, 1H), 7.47 (nfom, 1H), 7.30 (s, 1H), 7.29 (nfom, 1H), 6.24 (d,J=13.3 Hz, 1H), 6.05 (dd, 9.2, J=13.3 Hz, 1H), 4.93 (d, J=15.6 Hz, 1H),4.86 (dd, J=0.7, 15.6 Hz, 1H), 3.96 (dd, J=4.8, 11.1 Hz, 1H), 3.77 (dd,J=5.6, 11.2 Hz, 1H), 3.62 (nfom, 1H), and 0.42 [s, Si(CH₃)₃]. GC-MSt_(r)=13.48 min; m/z: 368, 353, 287, 257, 228, 202, 136, and 73.(Z)-4-(2-Chlorovinyl)-11-(trimethylsilyl)-3,4-dihydroindeno[1,2-g]isochromen-10(1H)-one:¹H NMR (500 MHz, CDCl₃): δ=7.59 (ddd, J=1.0, 1.0, 7.3 Hz, 1H), 7.48(nfom, 1H), 7.46 (nfom, 1H), 7.35 (s, 1H), 7.28 (nfom), 6.29 (d, J=7.1Hz, 1H), 5.96 (dd, J=7.1, 9.7 Hz, 1H), 4.94 (d, J=15.3 Hz, 1H), 4.87 (d,J=15.3 Hz, 1H), 4.25 (nfom, 1H), 4.00 (dd, J=4.9, 11.3 Hz, 1H), 3.73(dd, J=5.5, 11.3 Hz, 1H), and 0.42 [s, Si(CH₃)₃]. GC-MS t_(r)=13.52 min;m/z: 368, 353, 287, 257, 228, 202, 136, and 73.

Example 19

Spectral Data for Product of Example 19(1S,3aR,3bR,4aS)-3b-Phenyl-5-(trimethylsilyl)-4,4-a-dihydro-1H-1,3a-ethenocyclopropa[2,3]indeno[1,7-bc]fluoren-6(3bH)-one

¹H NMR (500 MHz, CDCl₃): δ=7.74 (d, J=7.5 Hz, 1H), 7.57 (d, J=7.4 Hz,1H), 4.45 (nfom, 3H), 7.39 (nfom, 2H), 7.30 (dddd, J=1.3, 1.3, 7.3, 7.3Hz, 1H), 7.22 (dd, J=7.4, 7.4 Hz, 1H), 7.06 (d, J=6.6 Hz, 1H), 6.90 (dd,J=5.8, 6.5 Hz, 1H), 6.73 (dd, J=5.5, 6.8 Hz, 1H), 6.69 (dd, J=1.4, 6.8Hz, 1H), 5.50 (dddd, J=1.5, 1.5, 5.5, 5.5 Hz, 1H), 3.20 (dd, J=3.8, 8.3Hz, 1H), 1.61 (dd, J=4.7, 8.2 Hz, 1H), 1.10 (dd, J=4.0, 4.5 Hz, 1H), and0.45 [s, Si(CH₃)₃]. GC-MS t_(r)=16.02 min; m/z: 442, 427, 401, 365, 324,313, 265, 162, and 73.

Example 20

Spectral Data for Product of Example 204-(Cyclopropylidenemethyl)-11-(trimethylsilyl)-3,4-dihydroindeno[1,2-g]isochromen-10(1H)-one

¹H NMR (500 MHz, CDCl₃): δ=7.58, (ddd, J=1.0, 1.0, 7.3 Hz, 1H), 7.48(nfom, 1H), 7.44 (nfom, 1H), 7.31 (d, J=0.9 Hz, 1H), 7.26 (nfom, 1H),5.88 (dtt, J=8.31, 2.0, 2.0 Hz, 1H), 4.93 (dd, J=1.4, 15.2 Hz, 1H), 4.89(dd, J=1.5, 15.1 Hz, 1H), 4.00 (dd, J=5.0, 10.8 Hz, 1H), 3.83 (nfom,1H), 3.77 (dd, J=6.7, 10.8 Hz, 1H), 1.26 (nfom, 1H), 0.88 (nfom, 1H),and 0.42 [s, Si(CH₃)₃]. GC-MS t_(r)=13.63 min; m/z: 360, 345, 330, 315,301, 287, and 275.

Example 21

Spectral Data for Product of Example 21(E)-4-((2,2-Diphenylcyclopropylidene)methyl)-11-(trimethylsilyl)-3,4-dihydroindeno[1,2-g]isochromen-10(1H)-one

¹H NMR (500 MHz, CDCl₃): δ=7.82 (nfom, 1H), 7.80 (nfom, 1H), 7.60 (nfom,1H), 7.54 (ddd, J=1.0, 1.0, 7.3 Hz, 1H), 7.49 (nfom, 2H), 7.40 (nfom,6H), 7.31 (nfom, 4H), 7.25 (nfom, 1H), 7.23 (ddd, J=1.0, 7.3, 7.3 Hz,1H), 6.95 (ddd, J=1.0, 1.0, 7.4 Hz, 1H), 4.92 (d, J=15.2 Hz), 4.88 (d,J=15.3 Hz, 1H), 4.07 (nfom, 1H), 3.80 (nfom, 1H), 2.31 (dd, J=2.0, 9.0Hz, 1H), 1.85 (dd, J=2.1, 9.0 Hz, 1H) and 0.41 [s, Si(CH₃)₃]. GC-MSt_(r)=13.68 min; m/z: 376, 361, 331, 287, 275, 215, 202, 136, and 73.

Example 22

Spectral Data for Product of Example 22

¹H NMR (500 MHz, CDCl₃): δ=7.90 (d, J=7.5 Hz, 1H), 7.63 (d, J=7.0 Hz,1H), 7.51 (dd, J=7.5, 7.5 Hz, 1H), 7.28 (dd, J=7.5, 7.5 Hz, 1H), 4.96(s, 1H), 4.79 (br s, 2H), 4.39 (br s, 2H), 1.99 (br s, 6H), and 0.36 (brs, 9H). ¹³C NMR (125 MHz, CDCl₃): δ=194.3, 149.8, 148.8, 144.6, 142.4,136.3, 136.0, 135.5, 135.1, 135.0, 134.4, 133.7, 128.3, 124.2, 121.8,71.2, 70.4, 56.2, 51.2, 20.0, and 2.3 ppm. IR (neat): 2950, 2903, 2849,1705, 1606, 1560, 1466, 1375, 1353, 1205, 1189, 1174, 1122, 1097, 995,and 942 cm⁻¹. HR ESI-MS: [C₂₆H₂₆O₂Si+Na]⁺ requires 421.1594. found421.1559.

Example 23

Spectral Data for Product of Example 23

¹H NMR (500 MHz, CDCl₃): δ=9.05 (d, J=8.0 Hz, 1H), 7.66 (ddd, J=8.0,1.5, and 0.5 Hz, 1H), 7.51 (ddd, J=8.0, 8.0, and 1.5 Hz, 1H), 7.32 (ddd,J=7.5, 7.5, and 0.5 Hz, 1H), 6.97 (dd, J=7.0, and 0.5 Hz, 1H), 6.87 (brs, 1H), 6.80 (dd, J=7.0, and 1.0 Hz, 1H), 5.56 (d, J=13.0 Hz, 1H), 5.53(d, J=13.0 Hz, 1H), and 0.34 (s, 9H).

Example 24

Spectral Data for Product of Example 24

¹H NMR (500 MHz, CDCl₃): δ=7.80 (s, 1H), 7.61 (ddd, J=7.0, 1.0, and 1.0Hz, 1H), 7.51 (ddd, J=7.5, 1.5, and 1.0 Hz, 1H), 7.47 (ddd, J=7.5, 7.5,and 1.5 Hz, 1H), 7.29 (ddd, J=7.0, 7.0, and 1.5 Hz, 1H), 6.82 (br s,1H), 6.74 (br s, 1H), 5.04 (br s, 2H), 2.67 (br s, 3H), 2.34 (br s, 3H)and 0.46 (s, 9H).

Example 25

Spectral Data for Product of Example 25

¹H NMR (500 MHz, CDCl₃): δ=7.76 (s, 1H), 7.61 (ddd, J=7.5, 1.0, and 1.0Hz, 1H), 7.50 (ddd, J=7.5, 1.5, and 1.0 Hz, 1H), 7.47 (ddd, J=7.0, 7.0,and 1.0 Hz, 1H), 7.29 (ddd, J=7.0, 7.0, and 1.5 Hz, 1H), 6.51 (dd, J=2.5and 0.5 Hz, 1H), 6.40 (dd, J=2.5 and 0.5 Hz, 1H), 5.04 (br s, 2H), 2.65(br s, 3H), 1.00 (s, 9H) and 0.45 (s, 9H).

Example 26

Spectral Data for the Product of Example 2611-(tert-Butyldimethylsilyl)-4-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-2,3-dihydroanthra[2,3-b]furan-5,10-dione

¹H NMR (500 MHz, CDCl₃): δ=8.23 (dd, J=8.0, 1.0 Hz, Ar—H), 8.09 (dd,J=8.0, 1.0 Hz, Ar—H), 7.72 (dd, J=8.0, 1.5 Hz, Ar—H), 7.70 (dd, J=8.0,1.5 Hz, Ar—H), 4.65 (t, J=9.0 Hz, ArOCH₂), 3.93 (t, J=7.5 Hz,OCH₂CH₂—C), 3.35 (t, J=9.0 Hz, ArCH₂CH₂O), 2.86 (t, J=7.5 Hz,OCH₂CH₂—C), 1.13 (s, C(CH₃)₃), 0.92 (s, C(CH₃)₃), 0.22 (s, tBuSi(CH₃)₂),0.11 (s, tBuSi(CH₃)₂). LC-MS: t_(r)=9.97 min; [M+H]⁺: 547.0

Example 27

Spectral Data for the Product of Example 27N,N-bis(7-Hydroxyhepta-2,4-diyn-1-yl)-4-methylbenzenesulfonamide

¹H NMR (500 MHz, CDCl₃): δ=7.74 (d, J=8.0 Hz, Ar—H), 7.30 (d, J=8.0 Hz,Ar—H), 6.45 (s, Ar—H), 4.54 (t, J=9.0 Hz, ArOCH₂), 4.52 (s, 2H), 4.49(s, 2H), 3.80 (br t, J=6.5 Hz, HOCH₂), 3.14 (t, J=9.0 Hz, ArCH₂CH₂O),2.70 (t, J=6.5 Hz, HOCH₂CH₂), 2.50 (t, J=6.5 Hz, OH), 2.38 (s, Ar—CH₃).LC-MS: t_(r)=3.05 min; [M+H]⁺: 384.1

Example 28

Spectral Data for the Product of Example 2811-(tert-butyldimethylsilyl)-5-(trimethylsilyl)-3,4,6,7,8,9-hexahydroindeno[1,2-g]chromen-10(2H)-one

¹H NMR (500 MHz, CDCl₃): δ=4.09 (t, J=5.5 Hz, CH₂O), 2.77 (t, J=5.5 Hz,ArCH₂), 2.57 [nfom, C═C(CH₂)—C═O], 2.22 (nfom, CH₂C═C—C═O), 1.90(pentet, J=5.5 Hz, ArCH₂CH₂CH₂O), 1.70 (m, CH₂CH₂CH₂CH₂), 0.97 (s,C(CH₃)₃), 0.41 (s, Si(CH₃)₃), and 0.29 (s, tBuSi(CH₃)₂). LC-MS:t_(r)=8.35 min; [M+H₃O]⁺: 443.2

Example 29

Spectral Data for the Product of Example 295,6-bis(trimethylsilyl)-7,8,9,10-tetrahydro-1H-1,4-ethenobenzo[a]fluoren-11(4H)-one

¹H NMR (500 MHz, CDCl₃): δ=6.75 (m, HC═CH), 5.99 (nfom, 1H), 5.11 (nfom,1H), 2.59 [nfom, C═C(CH₂)—C═O], 2.25 (nfom, CH₂C═C—C═O), 1.71 (m,CH₂CH₂CH₂CH₂), 0.42 (s, Si(CH₃)₃), and 0.31 (s, Si(CH₃)₃). LC-MS:t_(r)=6.57 min; [M+H]⁺: 405.1

Example 30

Spectral Data for the Product of Example 3010-(tert-butyldimethylsilyl)-2,3,6,7,8,9-hexahydro-4-(trimethylsilyl)fluoreno[3,2-b]furan-5-one

¹H NMR (500 MHz, CDCl₃): δ=4.42 (t, J=8.9 Hz, CH₂O), 3.15 (br t, J=8.9Hz, ArCH₂), 2.49 [nfom, C═C(CH₂)—C═O], 2.23 (nfom, CH₂C═C—C═O), 1.69 (m,CH₂CH ₂CH₂CH₂), 0.98 [s, C(CH₃)₃], 0.36 [s, tBuSi(CH₃)₂], and 0.36 [s,Si(CH₃)₃]. ¹³C NMR (125 MHz, CDCl₃): δ=198.2 (C═O), 169.1, 157.6, 154.9,136.2, 133.9, 130.6, 128.2, 70.2 (CH₂O), 31.3, 28.1 SiC(Me)₃, 27.5,23.2, 21.5, 20.2, 18.9 (CMe₃), 1.6, and 1.4. LC-MS: t_(r)=8.86 min;[M+H]⁺: 413.2

Example 31

Spectral Data for the Product of Example 3110-(tert-butyldimethylsilyl)-4-(trimethylsilyl)-3,5,6,7,8,9-hexahydro-2H-fluoreno[3,2-b]furan-5-ylacetate

LC-MS: t_(r)=12.6 min; [M-OAc]⁺: 397.0

Example 32

Spectral Data for the Product of Example 32 Ethyl8-(tert-butyldimethylsilyl)-2,3,5,7-tetrahydrobenzo[1,2-b:4,5-c′]difuran-4-carboxylate

¹H NMR (500 MHz, toluene-d8): δ=5.42 (t, J=2.0 Hz, 2H), 5.08 (br s, 2H),4.02 (t, J=9.0 Hz, OCH₂CH₂), 3.96 (q, J=7.5 Hz, OCH₂CH₃), 3.10 (t, J=9.0Hz, OCH₂CH₂), 0.96 (t, J=7.5 Hz, OCH₂CH₃) 1.77 (m, CH₂CH₂CH₂CH₂), 1.69(m, CH₂CH₂CH₂CH₂), 0.90 (s, C(CH₃)₃), and 0.26 (s, tBuSi(CH₃)₂). LC-MS:t_(r)=5.35 min; [M+H]⁺: 349.0

Example 33

Spectral Data for the Product of Example #33 Dimethyl5-(5-Hydroxypent-1-yn-1-yl)-3,4,6,8-tetrahydrocyclopenta[g]chromene-7,7(2H)-dicarboxylate

¹H NMR (500 MHz, CDCl₃): δ=6.59 (s, ArH), 4.09 (bt, J=5.1 Hz, CH₂OC),3.84 (t, J=6.2 Hz, CH₂OH), 3.75 (s, CO₂CH₃), 3.56 (s, C(CO₂Me)₂CH₂) 3.52(bs, C(CO₂Me)₂CH₂), 2.79 (bt, J=6.6 Hz, CCH₂CH₂CH₂OC), 2.60 (t, J=6.9Hz, CH₂CH₂CH₂OH) 1.97 (bp, J=6.5 Hz, CCH₂CH₂CH₂OC), and 1.88 (tt, J=6.7,6.4 Hz, CH₂CH₂CH₂OH). ¹³C NMR (500 MHz, CDCl₃): δ=172.2, 154.3, 138.2,134.2, 122.5, 119.8, 112.2, 97.5, 66.1, 61.8, 59.9, 53.0, 40.8, 40.1,31.7, 23.9, 22.2, and 16.3. IR (neat): 3458, 2951, 2876, 2229, 1734,1604, 1587, 1436, 1341, 1253, 1199, 1174, 1160, 1132, 1104, and 1060cm⁻¹. HR ESI-MS: C₂₁H₂₄O₆ [M+Na]⁺ requires 395.1465. found 395.1461

Example 34

Spectral Data for the Product of Example 345-(5-hydroxypent-1-yn-1-yl)-2,3,4,6,7,8-hexahydrocyclopenta[g]chromen-7-ylphenylcarbamate

¹H NMR (500 MHz, CDCl₃): δ=7.28-7.38 (m, 4H), 7.05 (tt, J=7.4 and 1.2Hz, 1H), 6.67 (s, CHCO), 6.56 (bs, NH), 5.55 (dddd, J=6.1, 6.1, 2.4, 2.4Hz, CHOC═O), 4.12 (bt, J=5.0 Hz, CH₂CH₂CH₂OC), 3.84 (t, J=6.2 Hz,CH₂CH₂CH₂OH), 3.277 (dd, J=17.0, 5.8 Hz, CH_(a)CHOC), 3.275 (dd, J=17.0,5.8 Hz, CH_(b)CHOC), 3.08 (dd, J=17.3, 2.2 Hz, CH_(a)CC_(ar)H) 3.03 (dd,J=17.0, 2.3, CH_(b)CC_(ar)H), 2.83 (bt, J=6.5 Hz, CH₂CH₂CH₂OC), 2.60 (t,J=6.9, CH₂CH₂CH₂OH), 2.00 (bp, J=6.5 Hz, CH₂CH₂CH₂OC), and 1.88 (t,J=6.8, 6.2 Hz, CH₂CH₂CH₂OH). GC-MS t_(r)=11.42 min; m/z: 413, 371, 295,267, 251, 235, 207, 191, 149, 103, and 59. HR ESI-MS: C₂₄H₂₅NO₄ [M+Na]⁺requires 414.1676. found 414.1716.

Example 35

Spectral Data for the Product of Example 35 Dimethyl6-Methoxy-5-(trimethylsilyl)-4-((trimethylsilyl)ethynyl)-1H-indene-2,2(3H)-dicarboxylate

¹H NMR (500 MHz, CDCl₃): δ=6.66 (s, ArH), 3.76 (s, CO₂CH₃), 3.72 (s,OCH₃), 3.59 (s, CH₂CCC≡C), 3.58 (s, CH₂CC_(aryl)H), 0.35 (s,C_(aryl)Si(CH₃)₃), and 0.24 (s, C≡CSi(CH₃)₃). LC-MS t_(r)=5.38 min;[M+1]⁺: 433.0

Example 36

Spectral Data for the Product of Example 36

¹H NMR (500 MHz, CDCl₃): δ=7.89 (d, J=0.5 Hz, 1H), 6.98 (dt, J=0.5 and1.0 Hz, 1H), 5.23 (d, J=1.0 Hz, 2H), 1.60 (s, 9H), and 0.29 (s, 9H). ¹³CNMR (125 MHz, CDCl₃): δ=171.2, 166.5, 150.5, 133.1, 133.0, 116.7, 106.4,79.7, 69.1, 28.9, and −1.0 ppm. IR (neat): 2978, 2952, 1750, 1606, 1583,1458, 1413, 1370, 1349, 1266, 1248, 1174, 1139, 1062, 1004, and 880cm⁻¹. HR ESI-MS: [C₁₅H₂₂O₃Si+Na]⁺ requires 301.1230. found 301.1181.

Example 37

Spectral Data for the Product of Example 37

¹H NMR (500 MHz, CDCl₃): δ=7.55 (d, J=7.3 Hz, ArHCC═O), 7.39-7.44 (m,2H), 7.25 (ddd, J=7.0, 7.0, 1.9 Hz, ArHCCCD), 4.21 (bt, J=5.1 Hz,CH₂OC), 2.88 (t, J=6.4 Hz, CH₂CH₂CH₂O), 2.01 (bp, J=6.4 Hz, CH₂CH₂CH₂O),and 0.43 [s, Si(CH₃)₃]. GC-MS t_(r)=12.34 min; m/z: 309, 294, 266, 208,179, 175, 147 and 73.

Example 38

Spectral Data for the Product of Example 386-oxo-5-(trimethylsilyl)-2,3,4,6-tetrahydroindeno[2,1-g]chromene-11-carbaldehyde

¹H NMR (500 MHz, CDCl₃): δ=10.61 (s, CHO), 8.23 (d, J=8.0 Hz, 1H), 7.58(dd, J=7.5, 0.5 Hz, 1H), 7.45 (ddd, J=7.6, 7.6, 1.3 Hz, 1H), 4.32 (t,J=5.0 Hz, CH₂CH₂CH₂Cl), 2.93 (t, J=6.4 Hz, CH₂CH₂CH₂Cl), and 2.06 (tt,J=6.4, 5.0 Hz, CH₂CH₂CH₂Cl), and 0.44 [s, Si(CH₃)₃]. GC-MS t_(r)=13.60min; m/z: 336, 321, 293, 265, 207, 178, 163, and 73.

Example 39

Spectral Data for the Product of Example 392-(3-Chloropropyl)-1-(trimethylsilyl)-9H-fluoren-9-one

¹H NMR (500 MHz, CDCl₃): δ=7.58 (d, J=7.3 Hz, ArHCC═O), 7.44-7.46 (m,3H, ArH), 7.23-7.27 (m, 2H, ArH), 3.55 (t, J=6.5 Hz, CH₂CH₂CH₂Cl), 2.95(bt, J=7.6 Hz, CH₂CH₂CH₂Cl), 2.00 (bp, J=6.4 Hz, CH₂CH₂CH₂Cl), and 0.44[s, Si(CH₃)₃]. HR ESI-MS: C₁₋₁₉H₂₁ClOSi [M+Na]⁺ requires 351.0942. found351.0969. GC-MS t_(r)=12.24 min; m/z: 328, 313, 277, 250, 235, 221, 203,189, 165, 139, and 73.

Example 40

Spectral Data for the Product of Example 408-(tert-Butyldimethylsilyl)-4-(3-((tert-butyldimethylsilyl)oxy)prop-1-yn-1-yl)-2H-indeno[5,6-b]furan-5(3H)-one

¹H NMR (500 MHz, CDCl₃): δ=7.49 (d, J=6.0 Hz, Ar—CH═), 5.83 (d, J=6.0Hz, ═CH—CO), 4.64 (s, OCH₂—C), 4.58 (t, J=9.0 Hz, CH₂CH₂O), 3.17 (t,J=9.0 Hz, C—CH₂), 0.94 (s, 9H), 0.90 (s, 9H), 0.36 (s, 6H), and 0.18 (s,6H). ¹³C NMR (125 MHz, CDCl₃): δ=195.7 (C═O), 169.5, 154.1, 148.0,127.5, 122.3, 117.5, 116.3, 97.0, 80.4, 79.5, 71.6 (OCH₂—C), 52.6(OCH₂CH₂), 28.7 (OCH₂CH₂), 26.6 (C(CH₃)₃), 25.9 (C(CH₃)₃), 18.4(C(CH₃)₃), 17.9 (C(CH₃)₃), −2.3 (Si(CH₃)₂), and −5.0 (Si(CH₃)₂).

Example 41

Spectral Data for the Product of Example 4110-(tert-Butyldimethylsilyl)-4-(trimethylsilyl)-5,6,7,8-tetrahydro-2H-fluoreno[2,3-b]furan-9(3H)-one

¹H NMR (500 MHz, CDCl₃): δ=4.37 (t, J=9.0 Hz, CH₂O), 3.15 (br t, J=9.0Hz, ArCH₂), 2.58 [nfom, C═C(CH₂)—C═O], 2.22 (nfom, CH₂C═C—C═O), 1.74 (m,CH₂CH₂CH₂CH₂), 1.68 (m, CH₂CH₂CH₂CH₂), 0.94 (s, C(CH₃)₃), 0.42 (s,Si(CH₃)₃), and 0.34 (s, tBuSi(CH₃)₂). LC-MS: t_(r)=7.93 min; [M+H₃O]⁺:429.1

Example 42

Spectral Data for the Product of Example 42tert-butyl((4-(8-(tert-Butyldimethylsilyl)-2,3,5,7-tetrahydrobenzo[1,2-b:4,5-e]difuran-4-yl)but-3-yn-1-yl)oxy)dimethylsilane

¹H NMR (500 MHz, CDCl₃): δ=5.06 (br s, 2H), 5.04 (br s, 2H), 4.52 (t,J=9.0 Hz, OCH₂CH₂—Ar), 3.80 (t, J=7.0 Hz, OCH₂CH₂—C), 3.16 (t, J=9.0H,OCH₂CH₂—Ar), 2.67 (t, J=7.0 Hz, OCH₂CH₂—C), 0.91 (s, C(CH₃)₃), 0.87 (s,C(CH₃)₃), 0.27 (s, tBuSi(CH₃)₂), 0.1 (s, tBuSi(CH₃)₂). LC-MS:t_(r)=10.51 min; [M+NH₄]⁺: 476.2

Example 43

Spectral Data for the Products of Example 438-(tert-Butyldimethylsilyl)-4-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-6,7-dihydro-2H-indeno[5,6-b]furan-5(3H)-one(Major)

¹H NMR (500 MHz, CDCl₃): δ=4.59 (t, J=8.5 Hz, OCH₂CH₂—Ar), 3.88 (t,J=7.5 Hz, OCH₂CH₂—C), 3.21 (t, J=8.5H, OCH₂CH₂—Ar), 3.02 (d, J=5.5 Hz)and 3.00 (d, J=5.5 Hz) [CH₂—C═O], 2.77 (t, J=7.5 Hz, OCH₂CH₂—C) 2.62 (d,J=5.5 Hz) and 2.61 (d, J=5.5 Hz) [CH₂CH₂—C═O], 0.90 (s, C(CH₃)₃), 0.89(s, C(CH₃)₃), 0.36 (s, tBuSi(CH₃)₂), 0.09 (s, tBuSi(CH₃)₂). LC-MS:t_(r)=7.84 min; [M+H]⁺: 471.1.

8-(tert-Butyldimethylsilyl)-4-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-5,6-dihydro-2H-indeno[5,6-b]furan-7(3H)-one(Minor)

¹H NMR (500 MHz, CDCl₃): δ=4.52 (t, J=8.5 Hz, OCH₂CH₂—Ar), 3.83 (t,J=7.5 Hz, OCH₂CH₂—C), 3.24 (t, J=8.5H, OCH₂CH₂—Ar), 3.00 (d, J=6.0 Hz)and 2.99 (d, J=6.0 Hz) [CH₂—C═O], 2.71 (t, J=7.5 Hz, OCH₂CH₂—C) 2.64 (d,J=6.0 Hz) and 2.62 (d, J=6.0 Hz) [CH₂CH₂—C═O], 0.93 (s, C(CH₃)₃), 0.92(s, C(CH₃)₃), 0.34 (s, tBuSi(CH₃)₂), 0.10 (s, tBuSi(CH₃)₂). LC-MS:t_(r)=6.65 min; [M+H]⁺: 471.1

Example 44

Spectral Data for the Products of Example 449-(tert-Butyldimethylsilyl)-5-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-3,4,7,8-tetrahydrocyclopenta[g]chromen-6(2H)-one(Major)

¹H NMR (500 MHz, CDCl₃): δ=4.13 (d, J=5.5 Hz, ArOCH₂) and 4.12 (d, J=5.5Hz, ArOCH₂), 3.90 (t, J=7.5 Hz, OCH₂CH₂—C), 3.01 (t, J=6.0 Hz)[CH₂—C═O], 2.89 (t, J=6.5 Hz, OCH₂CH₂CH₂—Ar), 2.69 (t, J=7.0 Hz,OCH₂CH₂—C), 2.59 (t, J=6.0 Hz) [CH₂CH₂—C═O], 1.98 (pentet, J=6.0 Hz,OCH₂CH₂CH₂—Ar), 0.91 (s, C(CH₃)₃), 0.90 (s, C(CH₃)₃), 0.35 (s,tBuSi(CH₃)₂), 0.09 (s, tBuSi(CH₃)₂).

8-(tert-Butyldimethylsilyl)-4-(5-((tert-butyldimethylsilyl)oxy)pent-1-yn-1-yl)-5,6-dihydro-2H-indeno[5,6-b]furan-7(3H)-one(Minor)

¹H NMR (500 MHz, CDCl₃): δ=4.52 (t, J=8.5 Hz, OCH₂CH₂—Ar), 3.77 (t,J=6.5 Hz, OCH₂CH₂CH₂), 3.23 (t, J=8.5H, OCH₂CH₂—Ar), 3.00 (t, J=6.0 Hz)[CH₂—C═O], 2.80 (t, J=7.0 Hz, OCH₂CH₂CH₂—C), 2.63 (d, J=6.0 Hz) and 2.62(d, J=6.0 Hz) [CH₂CH₂—C═O], 1.83 (pentet, J=6.0 Hz, CH₂CH₂CH₂—C), 0.92(s, C(CH₃)₃), 0.89 (s, C(CH₃)₃), 0.34 (s, tBuSi(CH₃)₂), 0.08 (s,tBuSi(CH₃)₂).

Example 45

Spectral Data for the Products of Example 458-(tert-Butyldimethylsilyl)-4-(5-((tert-butyldimethylsilyl)oxy)pent-1-yn-1-yl)-6,7-dihydro-2H-indeno[5,6-b]furan-5(3H)-one(Major)

¹H NMR (500 MHz, CDCl₃): δ=4.59 (t, J=8.5 Hz, OCH₂CH₂—Ar), 3.80 (t,J=6.0 Hz, OCH₂CH₂CH₂), 3.21 (t, J=8.5H, OCH₂CH₂—Ar), 3.01 (d, J=6.0 Hz)and 3.00 (d, J=6.0 Hz) [CH₂—C═O], 2.62 (t, J=7.0 Hz, OCH₂CH₂CH₂—C), 2.61(d, J=6.0 Hz) and 2.60 (d, J=6.0 Hz) [CH₂CH₂—C═O], 1.88 (pentet, J=6.0Hz, CH₂CH₂CH₂—C), 0.90 (s, C(CH₃)₃), 0.89 (s, C(CH₃)₃), 0.36 (s,tBuSi(CH₃)₂), 0.07 (s, tBuSi(CH₃)₂).

9-(tert-Butyldimethylsilyl)-5-(4-((tert-butyldimethylsilyl)oxy)but-1-yn-1-yl)-3,4,6,7-tetrahydrocyclopenta[g]chromen-8(2H)-one(Minor)

¹H NMR (500 MHz, CDCl₃): δ=4.08 (d, J=5.5 Hz, ArOCH₂) and 4.07 (d, J=5.5Hz, ArOCH₂), 3.84 (t, J=7.0 Hz, OCH₂CH₂—C), 3.01 (d, J=6.0 Hz) and 3.00(d, J=6.0 Hz) [CH₂—C═O], 2.94 (t, J=7.0 Hz, OCH₂CH₂CH₂—Ar), 2.73 (t,J=7.0 Hz, OCH₂CH₂—C), 2.61 (d, J=6.0 Hz) and 2.60 (d, J=6.0 Hz)[CH₂CH₂—C═O], 1.99 (pentet, J=6.5 Hz, OCH₂CH₂CH₂—Ar), 0.96 (s, C(CH₃)₃),0.92 (s, C(CH₃)₃), 0.30 (s, tBuSi(CH₃)₂), 0.10 (s, tBuSi(CH₃)₂).

Example 46

Spectral Data for Product of Example 46

¹H NMR (500 MHz, CDCl₃): δ=7.53 (ddd, J=7.5, 1.0, and 1.0 Hz, 1H), 7.42(ddd, J=7.0, 7.0, and 1.0 Hz, 1H), 7.40 (ddd, J=6.0 and 1.0 Hz, 1H),7.24 (ddd, J=7.0, 7.0, and 1.5 Hz, 1H), 6.99 (s, 1H), 6.10 (ddt, J=17.3,10.6, and 4.9 Hz, 1H), 5.49 (ddt, J=17.0, 1.5, and 1.5 Hz, 1H), 5.35(ddt, J=10.6, 1.5, and 1.5 Hz), 4.68 (ddd, J=4.5, 1.5, and 1.5 Hz, 2H),4.12 (t, J=6.5 Hz, 2H), 2.91 (br t, J=8.5 Hz, 2H), 2.07 (s, 3H), 1.82(m, 2H), and 0.45 (s, 9H).

Example 47

Spectral Data for Product of Example 47

¹H NMR (500 MHz, CDCl₃): δ=7.54 (d, J=7.5 Hz, 1H), 7.42 (dd, J=7.5 and7.5 Hz, 1H), 7.38 (d, J=7.0 Hz, 1H), 7.24 (dd, J=7.0 and 7.0 Hz, 1H),7.17 (s, 1H), 4.11 (t, J=6.5 Hz, 2H), 2.85 (br t, J=8.0 Hz, 2H), 2.06(s, 3H), 1.78 (m, 2H), and 0.44 (s, 914). ¹³C NMR (125 MHz, CDCl₃):δ=194.2, 171.3, 159.5, 145.5, 143.51, 143.49, 140.7, 134.8, 134.0,132.6, 128.9, 123.6, 119.0, 110.7, 80.0, 64.7, 30.8, 29.5, 26.8, 21.2,and 2.8 ppm. IR (neat): 2977, 2949, 1738, 1706, 1605, 1582, 1550, 1466,1391, 1365, 1293, 1239, 1163, 1127, 1038, 998, and 948 cm⁻¹. HR ESI-MS:[C₂₅H₃₂O₄Si+Na]⁺ requires 447.1962. found 447.1979.

Example 48

Spectral Data for Product of Example 48

¹H NMR (500 MHz, CDCl₃): δ=7.54 (d, J=7.0 Hz, 1H), 7.43 (dd, J=7.5 and7.5 Hz, 1H), 7.37 (d, J=7.5 Hz, 1H), 7.26 (m, overlapped with CHCl₃peak), 6.93 (s, 1H), 4.14 (t, J=6.5 Hz, 2H), 2.88 (br t, J=8.0 Hz, 2H),2.09 (s, 3H), 1.89-1.82 (m, 2H), and 0.46 (s, 9H).

Example 49

Spectral Data for Product of Example 49

¹H NMR (500 MHz, CDCl₃): δ=7.58 (d, J=7.5 Hz, 1H), 7.46 (ddd, J=7.5, 7.5and 1.0 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H), 7.28 (ddd, J=7.5, 7.5, and 1.0Hz, 1H), 7.22 (s, 1H), 4.11 (t, J=6.5 Hz, 2H), 2.78 (br t, J=8.5 Hz,2H), 2.39 (s, 3H), 2.08 (s, 3H), 1.82-1.75 (m, 2H), and 0.46 (s, 9H).¹³C NMR (125 MHz, CDCl₃): δ=194.1, 171.0, 169.2, 153.0, 145.0, 142.2,142.9, 139.9, 137.7, 134.5, 134.0, 129.2, 123.9, 119.8, 115.8, 64.0,30.9, 26.2, 21.04, 20.98 and 2.6 ppm. IR (neat): 2949, 1759, 1739, 1713,1605, 1591, 1467, 1387, 1366, 1295, 1243, 1201, 1159, 1118, 1039, 995,and 854 cm⁻¹. HR ESI-MS: [C₂₃H₂₆O₅Si+Na]⁺ requires 433.1441. found433,1436.

Example 50

Spectral Data for Product of Example 50

¹H NMR (500 MHz, CDCl₃): δ=7.61 (ddd, J=7.5, 1.0 and 1.0 Hz, 1H), 7.46(ddd, J=7.5, 7.5, and 1.0 Hz, 1H), 7.41 (ddd, J=7.5, 1.0, and 0.5 Hz,1H), 7.40 (s, 1H), 7.32 (ddd, J=8.0, 8.0, and 1.0 Hz, 1H), 7.28 (ddd,J=7.5, 7.5, and 1.0 Hz, 1H), 7.15 (dd, 7.5 and 2.0 Hz, 1H), 7.03 (ddd,J=7.5, 7.5, and 1.0 Hz, 1H), 7.01 (dd, J=8.0 and 1.0 Hz, 1H), 4.84 (s,1H), 3.82 (br t, J=6.0 Hz, 2H), 2.87 (ddd, J=14.0, 11.5, and 5.5 Hz,1H), 2.65 (ddd, J=13.5, 11.0, and 5.5 Hz, 1H), 1.87 (s, 3H), 1.62 (m,2H), and 0.49 (s, 9H). ¹³C NMR (125 MHz, CDCl₃): δ=195.1, 171.1, 152.2,148.5, 143.60, 143.59, 143.4, 142.0, 140.7, 134.8, 134.0, 130.2, 129.7,129.2, 128.4, 124.2, 123.9, 121.0, 119.8, 115.9, 63.8, 32.1, 29.8, 29.4,21.0, and 2.9 ppm. IR (neat): 3440, 2951, 1736, 1710, 1606, 1590, 1541,1464, 1448, 1386, 1363, 1247, 1185, 1040, and 979 cm⁻¹. HR ESI-MS:[C₂₇H₂₈O₄Si+Na]⁺ requires 467.1649. found 467.1647

Example 51

Spectral Data for Product of Example 51

¹H NMR (500 MHz, CDCl₃): δ=7.61 (ddd, J=7.5, 1.0 and 1.0 Hz, 1H), 7.45(ddd, J=7.5, 7.5 and 1.0 Hz, 1H), 7.41 (ddd, J=7.0, 1.0, and 1.0 Hz,1H), 7.38 (s, 1H), 7.28 (ddd, J=7.5, 7.5, and 1.0 Hz, 1H), 7.11 (dd,J=8.5 and 2.0 Hz, 1H), 6.95 (d, J=2.0 Hz, 1H), 6.90 (d, J=8.0 Hz, 1H),4.69 (s, 1H), 3.84 (br t, J=6.5 Hz, 2H), 2.86 (ddd, J=13.5, 11.0, and5.5 Hz, 1H), 2.67 (ddd, J=13.5, 11.0, and 5.5 Hz, 1H), 2.33 (dd, J=0.7and 0.7 Hz, 3H), 1.88 (s, 3H), 1.70-1.56 (m, 2H), and 0.49 (s, 9H).

Example 52

Spectral Data for Product of Example 52

¹H NMR (500 MHz, CDCl₃): δ=7.55 (ddd, J=7.5, 1.0 and 1.0 Hz, 1H), 7.41(ddd, J=7.5, 7.5, and 1.0 Hz, 1H), 7.32 (ddd, J=7.0, 1.0, and 1.0 Hz,1H), 7.22 (ddd, J=7.5, 7.5, and 1.0 Hz, 1H), 4.12 (br t, J=6.5 Hz, 2H),3.31 (dd, J=4.0 and 1.0 Hz, 1H), 3.39 (dd, J=4.0 and 1.0 Hz, 1H), 2.71(br t, J=8.0 Hz, 2H), 2.47 (br s, 1H), 2.37 (br s, 1H), 2.08 (s, 3H),1.88-1.72 (m, 2H), 1.72-1.62 (m, 2H), 1.31-1.22 (m, 2H), 1.10 (br s,2H), and 0.42 (s, 9H). ¹³C NMR (125 MHz, CDCl₃): δ=195.4, 171.2, 152.4,143.1, 142.0, 140.7, 140.4, 140.3, 137.5, 134.6, 134.3, 128.6, 124.0,121.5, 64.2, 52.1, 48.6, 36.5, 35.9, 32.7, 32.0, 28.0, 27.8, 27.7, 21.1,and 2.7 ppm. IR (neat): 2948, 2872, 1740, 1708, 1605, 1571, 1464, 1386,1364, 1293, 1237, 1182, 1173, 1079, 1042, 997, 998, 950, and 917 cm⁻¹.HR ESI-MS: [C₂₈H₃₂O₃Si+Na]⁺ requires 467.2013. found 467.2027

Example 53

Spectral Data for Product of Example 53

¹H NMR (500 MHz, CD₃OD): δ=7.59 (br d, J=7.5 Hz, 1H), 7.58 (d, J=7.5,1H), 7.53 (br dd, J=7.5 and 7.5 Hz, 1H), 7.51 (ddd, J=7.5, 7.5, and 1.0Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.29 (ddd, J=7.5, 7.5, and 1.0 Hz, 1H),4.10 (t, J=6.5 Hz, 2H), 2.88 (br t, J=8.0 Hz, 2H), 2.04 (s, 3H), 1.86(m, 2H), and 0.43 (s, 9H). HR ESI-MS: [C₂₁H₂₄O₃Si+Na]⁺ requires375.1387. found 375.1386.

Example 54

Spectral Data for Product of Example 54

Major Isomer

¹H NMR (500 MHz, CDCl₃): δ=7.76 (s, 1H), 7.60 (d, J=7.5 Hz, 1H), 7.48(dd, J=7.0 and 7.0 Hz, 1H), 7.44 (d, J=7.5 Hz, 1H), 7.30 (dd, J=7.5 and7.5 Hz), 4.17 (br t, J=6.5 Hz, 2H), 3.09 (br t, J=8.5 Hz, 2H), 2.08 (s,3H), 1.90-1.80 (m, 2H), and 0.46 (s, 9H).

Minor Isomer

¹H NMR (500 MHz, CDCl₃): δ=8.32 (d, J=7.5 Hz, 1H), 7.63 (d, J=7.0 Hz,1H), 7.55-7.48 (m, overlapped with major isomer peaks, 2H), 7.39 (s,1H), 7.32 (dd, J=8.0 and 8.0 Hz, 1H), 4.12 (br t, J=6.5 Hz, 2H), 2.83(br t, J=8.0 Hz, 2H), 2.08 (s, 3H), 1.90-1.80 (m, 2H), and 0.43 (s, 9H).

Example 55

Spectral Data for Product of Example 55

¹H NMR (500 MHz, CDCl₃): δ=7.60 (ddd, J=7.5, 1.0 and 1.0 Hz, 1H), 7.55(s, 1H), 7.48 (ddd, J=7.5, 7.5, and 1.0 Hz, 1H), 7.44 (ddd, J=7.5, 1.5,and 1.0 Hz, 1H), 7.30 (ddd, J=7.0, 7.0, and 1.0 Hz, 1H), 4.16 (t, J=6.5Hz, 2H), 3.05 (br t, J=8.5 Hz, 2H), 2.08 (s, 3H), 1.88-1.82 (m, 2H), and0.47 (s, 9H).

The starting polyalkynes used in the above reactions can be preparedusing methods known in the field of organic chemistry, or they can beprepared using methods similar to those described in Schemes 5-8 herein.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A method comprising cyclizing a compoundincluding three triple bonds, wherein two of the triple bonds are in aconjugated butadiyne subunit at a temperature below about 300° C. toprovide a polycyclic compound having four carbon atoms from the twotriple bonds that were in the conjugated butadiyne subunit present in asix-membered carbocyclic ring of the polycyclic compound.
 2. A methodcomprising cyclizing a nonaromatic compound including three triplebonds, wherein two of the triple bonds are in a conjugated butadiynesubunit at a temperature below about 300° C. to provide a polycycliccompound having four carbon atoms from the two triple bonds that were inthe conjugated butadiyne subunit present in a six-membered carbocyclicring of the polycyclic compound.
 3. The method of claim 1 furthercomprising contacting the polycyclic compound with a benzyne trappingreagent.
 4. The method of claim 3 wherein the benzyne trapping reagentis a phenol, a furan, cyclooctane, cycloheptane, an alcohol, benzene, ora substituted benzene derivative.
 5. The method of claim 3 wherein thebenzyne trapping reagent is an aromatic agent, a formal hydrogenmolecule (H₂) donor, an oxygen-based nucleophile of protic or aproticnature, a sulfur containing nucleophile, a selenium-containingnucleophile, a phosphorous-containing nucleophile, a nitrogen-containingnucleophile, a halogen source, a metal halide salt, a hydrogen halide,an ammonium halide, a halosilane, an alkyl halide, or a pi-bondcycloaddend.
 6. A polycyclic compound prepared according to the methodof claim 3.